Prostate carcinogenesis likely involves a complex interplay between inherited genetic susceptibility and exogenous and endogenous exposures. Based on our current understanding of prostate carcinogenesis, we propose a hybrid case-only/case-control study designed to measure the joint effects of putative genetic and environmental risk factors. We plan to enroll 440 incident prostate cancer cases under age 70 and 220 race and age frequency-matched healthy controls. This study will be carried out in a population evenly divided between Caucasians and African-Americans, so that race-specific risk factors and interactions can be identified. The main goals of our study are: 1) to determine whether selected occupational (i.e., cadmium, zinc and polycyclic hydrocarbons), environmental (i.e., diet, ultraviolet radiation), lifestyle (i.e., physical activity) and genetic (i.e., CYP17, CYP3A4, GSTP1, SRD5A2, vitamin D receptor, androgen receptor, metallothionein 2A, HSD3B2polyhmorphisms) risk factors are associated with increased risk for prostate cancer; and 2) to test combinations of the above genetic and environmental risk factors for putative gene-environment and gene-gene interactions based on their posited role in prostate carcinogenesis. The inclusion of controls in our study design will allow us to estimate main effects and test whether genetic and environmental risk factors are independent. If the latter is true, then we can use our larger case sample to test for specific gene-environment interactions based on biologically plausible scenarios. The analysis will be conducted using log-linear models, which uniquely allow us to include or exclude control data depending upon our specific analytic goals (e.g., estimation of main effects vs. interaction terms). This study will be the first known effort specifically designed to test for gene-environmental interaction in prostate carcinogenesis.